Given the central role of T-cells in transplant rejection, a common goal among current immunosuppressive therapies is to block T-cell activation and function (Sayegh, M. H. et al., N. Engl. J. Med., 338(25):1813-1821 (1998)). T-cells require both an antigen-specific (Signal 1) and co-stimulatory signal (Signal 2) for full activation (Lenschow, D. J. et al., Annu. Rev. Immunol., 14:233-258 (1996)). One of the best-characterized co-stimulatory pathways involves the CD28-CD80/86 (B7-1/2) interaction (Linsley, P. S. et al., Annu. Rev. Immunol., 11:191-212 (1993)). Cytotoxic T-lymphocyte antigen 4 (CTLA4) binds to CD80/86 with higher avidity than CD28, and is transiently expressed on T-cells following their activation, where it interrupts the interaction between CD28 and CD80/86 (Oosterwegel, M. A. et al., Curr. Opin. Immunol., 11(3):294-300 (1999)). This creates a negative feedback signal for T-cell activation.
Functionally distinct T cell populations can be defined by the expression of specific cell surface antigens. Numerous studies describe associations between T cell surface phenotype and function (Appay, V. et al., Nat. Med., 8:379-385 (2002)). CD57, a surface molecule expressed on T and NK cells, is a marker with functional associations. CD57 has been commonly described as an external marker of cell senescence, a state in which the cell is in persistent cell cycle arrest. Expansions of CD4+ T cells expressing CD57 have been associated with a number of chronic pathological conditions such as tuberculosis, malaria, rheumatoid arthritis, and HIV-1 infection (Maeda, T. et al., Arthritis Rheum., 46:379-384 (2002); Imberti, L. et al., Blood, 89:2822-2832 (1997)).
Belatacept (L104EA29YIg) is the first biologic agent approved for primary maintenance immunosuppression, selectively blocking the CD28 co-stimulation pathway to prevent T-cell activation (Larsen, C. P. et al., Am. J. Transplant., 5:443-453 (2005)). Belatacept combined with corticosteroids and a mycophenolic acid is indicated for prophylaxis of graft rejection in adults receiving a renal transplant. While Belatacept has been associated with improved long-term graft function as well as patient and graft survival, patients treated with this costimulation blockade molecule tended to experience early acute rejection.
Further, while the introduction of kidneys from extended criteria donors has been necessary to alleviate donor organ shortages, recipients are at greater risk of complications and graft loss than recipients of living or standard criteria deceased donor kidneys (Tullius, S. G. et al., Eur. Renal Dis., 1:51-54 (2007)).
With the increasing use of costimulation blockade molecules and higher risk extended criteria donor organs, it is clear that there is a need to prospectively identify patients at risk for costimulation blockade resistant rejection. The Inventors have identified a CD4+ T cell phenotype that strongly correlates with risk for costimulation blockade resistant rejection.
At present, there are no predictive assays to identify patients at risk of costimulation blockade resistant rejection. Thus, there is a need in the art for a diagnostic assay that could determine whether a patient would be eligible to be treated with costimulation blockade molecules or at risk of acute rejection. The present invention provides such novel assay.